Biomedical Engineering Trends in Materials Science Part 18 potx

Biomedical Engineering, Trends in Materials Science 502 N N N R 1 R 1 N N N +H R 2 Cu(I) catalyst R 2 Fig. 17. Copper(I)-catalyzed alkyne-azide cycloaddition The use of click chemistry for the functionalization of polyesters has also been reported for block copolymerization and for the synthesis of star-shaped polymers (Lecomte et al. 2008), but the most interesting strategies remain the grafting onto and grafting through approaches. The latter will be briefly described in the next paragraph. For the grafting onto strategy, cyclic esters bearing an azide or alkyne functional group are synthesized in the first step, followed by ring-opening polymerization and the grafting of an azide or alkyne end- capped polymer onto the functionalized polyester backbone. Parrish et al. (2005) pioneered this approach synthesizing a α-propargyl-δ-valerolactone that was further copolymerized with ε-caprolactone (Fig. 18). The resulting alkyne grafted aliphatic polyester served as backbone for clicking oligopeptide moities and poly(ethylene glycol) onto the backbone. The synthesis of other monomers of interest such as α-azide-ε- caprolactone (Riva et al., 2005) and 3,6-dipropargyl-1,4-dioxane-2,5-dione (Jiang et al., 2008) and subsequent polymerization and grafting have also been reported in the literature, leading notably to poly(ethylene glycol)-graft-poly(ε-caprolactone) and –polylactides, respectively. Note that the reactive groups used for the grafting onto method can also be introduced by post-polymerization modification of a chloro-functionalized polyester backbone (Riva et al., 2005). 2.3.4 Grafting through methods In this approach, a cyclic ester bearing a pendant macromolecular chain is synthesized and polymerized. Poly(ethylene glycol) chains end-capped by an ε-caprolactone unit have been synthesized by living anionic ring-opening polymerization of ethylene oxide initiated by the potassium alkoxide of 1,4-dioxaspiro[4,5]decan-8-ol, followed by derivatization of the acetal into a ketone and the Baeyer-Villiger oxidation of the ketone into a lactone (Rieger et al., 2004). The polymerization of this monomer lead to poly(ethylene glycol)-graft-poly(ε- caprolactone). This is represented in Fig. 19. Click chemistry can also be used for the synthesis of poly(ethylene glycol) macromonomers based on ε-caprolactone and lactide (Riva et al., 2005 and Jiang et al., 2008, respectively). 3. Polycondensation (Fig. 20) The synthesis of polyesters can take place by polycondensation of diols with diacids (AA – BB) or by the polycondensation of hydroxyacids (AB), leading to the formation of water as by-product. The reaction often takes place under vacuum to remove the water formed. High molecular weights are generally difficult to achieve. The section begins with the description of melt/solid polycondensation, a strategy developed to obtain high molecular weight poly(lactid acid) and poly(glycolic acid). The introduction of functional groups into polyesters by polycondensation is rendered difficult by the sensitivity of the functional groups, often secondary alcohols, to the polymerization. The brief description of protection Synthetic Strategies for Biomedical Polyesters Specialties 503 O O lithium N,N'-diisopropylamide, THF Br O O ε-caprolacone Sn(OTf 2 )-EtOH RT, 48h O O OH O O n n (1) GRGDS - Resin Br O OH + Br O O GRGDS 1. N,N'- diisopropylcarbodiimide 1-hydroxybenzotriazole 2. cleavage - deprotection NaN 3 N 3 O GRGDS (2) O O OH O O n n N N N GRGDS (1) + (2) CuSO 4 .5H 2 O Sodium ascorbate Fig. 18. Synthesis of oligopeptide-graft-aliphatic polyester via click chemistry and grafting onto approach (Parrish et al., 2005) - GRDS is an oligopeptide sequence. Biomedical Engineering, Trends in Materials Science 504 O O O O m-chloroperoxy- benzoic acid ROH Al(Et) 3 RO O O O H n OMe OMen n OO LiAlH 4 OH OO 1. KOH toluene 2. EO toluene OO O O - n CH 3 I OO O OMe n HCl O OMe n O Fig. 19. Synthesis of poly(ethylene glycol)-graft-poly(ε-caprolactone) copolymers via the grafting through method (Rieger et al., 2004). EO = ethylene oxide. Synthetic Strategies for Biomedical Polyesters Specialties 505 n nHO FG OH + FG O FG O FG O O OHnHO O O Polycondensation (Protection - Deprotection) +H 2 O Fig. 20. Polycondensation. FG represents a functional group. strategies used for this purpose is followed by recent advances in one-step strategies enabling the functionalization of polyesters by polycondensation without the need to protect the functional group, i.e enzymatic and Lewis acid catalysis. Note that these one-pot strategies lead to polyesters bearing multiple functional groups along the polymeric backbone. 3.1 Melt and solid polycondensation The acid form of ε-caprolactone, 6-hydroxyhexanoic acid, is scarcely isolable, and thus, poly(ε-caprolactone) is rarely synthesized by polycondensation techniques. Lactic and glycolic acids are in turn naturally occurring products, and their polymers and copolymers can also be made via polycondensation. A major drawback is the removal of the water formed during the polymerization, leading often to modest number-average molecular weight. This drawback can be overcome via melt and solid polycondensation techniques. Melt polycondensation is conducted under reduced pressure at high temperature, starting from oligomers of the targeted polymer. One may distinguish melt polycondensation from solid polycondensation; in the former case, the polymerization is conducted at a temperature above the melting temperature of the polymer. For example, the melt polycondensation of oligo(L-lactic acid) was conducted using SnCl 2 combined to protonic acids such as p-toluenesulfonic acid monohydrate or m-phosphoric acid (Moon et al., 2000). Weight average molecular weights up to 100 000 g/mol were obtained. The crystallization of the so-obtained poly(L-lactic acid) and subsequent solid polycondensation at temperature below the melting temperature lead to weight average molecular weights up to 500 000 g/mol using similar catalytic systems (Moon et al., 2001). Melt/solid polycondensation can also be applied to oligo(glycolic acid) (Takahashi et al., 2000). 3.2 Protected monomers The introduction of functional groups such as secondary hydroxyls is rendered difficult by the possible reaction of these groups with the acid functionality, leading to cross-linking and gelation. The strategy consists thus usually in the protection of secondary alcohols on a functional compound, or to the synthesis of monomers where the secondary hydroxyl functions are protected. There are numerous works dealing with the synthesis of new Biomedical Engineering, Trends in Materials Science 506 monomers with protected functional groups, often starting from carbohydrate derivatives. For example, protected gluconic acid in the form of 2,4,3,5-di-O-methylene-D-gluconic acid can by polymerized with benzoyl chloride (Mehltretter & Mellies 1955). The same strategy can also be applied to AA-BB polycondensation (Metzke et al., 2003, among others). 3.3 One step introduction of functional groups into polyesters The synthesis of linear polyesters via one step polycondensation of monomers bearing secondary pendant hydroxyl groups relies on the selectivity of specific catalysts toward primary alcohols. Using such catalysts, the acid functionality reacts with primary alcohols, but not with lateral secondary alcohols, avoiding cross-linking and gelation. This can be done by enzymatic and Lewis acid catalysis. HO (CH 2 ) r OH OH O O O O r (H 2 C)O O O OH O + m n n Lipase 50°C, 24h +(2n-1) CH 2 =CHOH CH 3 CHO O (CH 2 ) r OH O O O O(CH 2 ) r HO O O p q Fig. 21. Lipase catalyzed regioselective polycondensation between triols and divinyl adipate. R=1, glycerol, R=2, 1,2,4-butanetriol, and R=4, 1,2,6 trihydroxyhexane (Kline et al., 1998) Synthetic Strategies for Biomedical Polyesters Specialties 507 3.3.1 Enzymatic catalysis Enzymatic catalyzed polycondensation enables a one-step synthesis of hydroxyl pendant polyesters using renewable resources as the polyol monomer. Using Novozyme-435 lipase and Candida antartica lipase B, glycerol, 1,2,4-butanetriol and 1,2,6 trihydroxyhexane can be copolymerized with divinyl esters to yield low to high molecular weight linear hydroxypolyesters (Kline et al. 1998, Uyama et al. 2001 – Fig. 21). The reaction is regioselective, as the pendant hydroxyl groups in the polymer are mainly secondary. Glycerol can also be copolymerized with adipic acid and 1,8-octanetriol using Novozyme- 435, yielding a few intermolecular crosslinks in addition to hydroxyl pendant groups (Kumar et al. 2003). Carbohydrate polyols such as sorbitol (Fig. 22) and alditols were also successfully copolymerized with 1,8-octanediol and adipic acid using the aforementioned enzyme as catalyst (Kumar et al., 2003, Hu et al., 2006). 3.3.2 Lewis acid catalysis Lewis acid catalyzed polyesterification is another type of chemistry enabling a one step synthesis of linear polyesters bearing pendant hydroxyl groups. Using trifluoromethane sulfonate salts (known as triflate - M(OSO 2 CF 3 ) n ), sorbitol and glycerol were successfully copolymerized with diacids (Takasu et al. 2007). Lewis acid catalysis is rather versatile as diacids bearing pendant hydroxyl groups such as tartaric and malic acids could also be copolymerized selectively with diols in bulk and under reduced pressure. The resulting polyesters had low to average molecular weights. The procedures are represented in Fig. 23. HOH 2 C CH 2 OH OH OH OH OH HOOC COOH 2 HOH 2 C CH 2 OH 6 ++ Novozyme 435 42h, 90°C Bulk, vacuum OH OH OH OH O O O O O 2 O O O 6 2 m p Fig. 22. Novozyme-435-catalyzed regioselective polymerization of sorbitol with adipic acid and 1,8-octanetriol (Kumar et al., 2003) Biomedical Engineering, Trends in Materials Science 508 HO O R 1 R 2 O OH HO R 3 OH n Succinic acid R 1 =H, R 2 =H Malic acid R 1 =OH, R 2 =H Tartatic acid R 1 =H, R 2 =OH + n=1,4,7,9 R 3 =H, OH O R 1 R 2 O O R 3 O n m R 1 ,R 2 ,R 3 =OHorH Sc(OTf) 3 60-80°C Reduced pressure Fig. 23. Scandium triflate catalyzed regioselective polycondensation of dicarboxylic acids and diols having pendant hydroxyl groups (Takasu et al., 2007) 4. Transesterification The principle of transesterification is presented in Fig. 24. The reaction can start from an ester and an alcohol, or from two ester groups. Transesterification commonly occurs in the molten state, producing first block copolymers and finally statistical copolymers. + Transesterification Polymer 1 Polymer 2 Mutliblock copolymer Fig. 24. Transesterification Transesterification of poly(D,L-lactide) and polyethylene glycol was reported in acetone, without catalysts, leading to copolymers with number-average molecular weights up to 6000 g/mol (Piskin et al., 1995). The polymer precursors exhibit number average molecular weights between 2000 and 4000 g/mol. Additional purification steps are necessary in order to remove the remaining homopolymer. The resulting copolymer was shown to form micelles, poly(D,L-lactide) being the hydrophobic segment and polyethylene glycol the hydrophilic segment, and were further used as drug carriers. The composition of the copolymer can be simply changed by varying the ratio of polymer precursors. The molecular weight of the resulting copolymer can be significantly increased starting from precursors of higher molecular weight. Using succinic acid as chain extender for poylethylene glycol, poly(L-lactide) and poly(D,L-lactide) of high molecular weight and titanium isopropoxyde as transesterification catalyst, molecular weight up to 40 000 g/mol vs. polystyrene standards could be achieved (Mai et al. 2009). Synthetic Strategies for Biomedical Polyesters Specialties 509 5. Conclusion The synthetic strategies for the functionalization of polyesters are numerous, and result in a great diversity of polyesters specialties for potential biomedical applications. Various architectures can be synthesized, including statistical and block copolymers, as well as graft and star-shape copolymers. Ring-opening polymerization leads generally to higher molecular weights than polycondensation, and has been more studied. Enzymatic and organocatalyzed ring-opening polymerization are particularly interesting, as they enable one-pot regioselective end-functionalizations of polyesters by carbohydrate derivatives notably, without protection/deprotection steps. Regioselective polymerization can also be conducted by polycondensation, considering enzymatic and Lewis acid catalysis. This leads to a higher number of functionalities along the polymeric backbone, which can only be achieved by protection / deprotection strategies or derivatization considering ring-opening polymerization. Transesterification leads on the other side to interesting microstructures, and can be conducted without catalysts in certain conditions. 6. Acknowledgments Drs. Till Bousquet and Andreia Valente are gratefully acknowledged for careful reading. 7. References Albertsson, A.C.; Varm I.K. (2003) Recent developments in ring opening polymerization of lactones for biomedical applications. Biomacromolecules. Vol. 4, 1466-1486. 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Vol. 42, 2577-2588 [...]... risk for emergence of infections Recent research showed that 518 518 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science biofilms are involved in 65% of microbial infections in the body (Potera, 1999), such as urinary tract infections, catheter associated and middle-ear infections, formation of dental plaque, gingivitis, coating contact lenses, and... eliminate it from the body (Lyu and Untereker, 2009) The oxidation mechanism begins with the increasing number of free radicals due to the oxygen adsorbed from the surrounding tissues or blood The oxygen 522 522 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science molecules react with the existing free radicals (Lyu and Untereker, 2009), resulting in. .. mechanical forces during their use, and therefore excellent mechanical properties are key requirements These materials are usually knee and hip joints or other kinds of orthopaedic implants The most common failures of these materials are wearing, breaking or cracking and erosion 524 524 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science (Göpferich,... application point of view causes decreased service time An example for body reaction is the formation of carboxylic acid, which 526 526 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science changes the local pH, causing inflammatory response As an example during the production of some polyurethanes, methylene diamine is used, which is a toxic compound In case... antibiotics or antimicrobial metallic particles are incorporated into the structure of HA the risk for infections and biofilm formation can be decreased The trials showed that silver and antibiotics loaded HA coatings express superior antimicrobial properties on short term and 530 530 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science due to the slow release... surface in an aqueous environment (Lynch 514 514 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science et al., 2003) In general, biofilms can host microorganisms such as bacteria, fungi, protozoa, algae and their mixtures, and usually the constituent cells require similar conditions to initiate and progress the cell growth The factors that influence... sutures and resorbable bone plates 520 520 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science 4 Degradation mechanisms of medical polymers The human body contains a variety of enzymes and chemicals that may cause degradation of the polymer (Williams, 1992, Williams, 1991) Polymers containing ester or amide linkages (i.e polyurethane) are more likely... Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science against specific antibiotics (e.g MRSA: Methicillin-Resistant Staphylococcus aureus) or in extreme cases this resistance can expand to several groups of drugs During the improvement and development of antimicrobial and antiseptic materials that inhibit the biofilm formation and infections, these factors... Waals force Primary attraction 516 516 Biomedical Engineering, Trends in Materials Science Biomedical Engineering, Trends in Materials Science Approximate interaction energy (kJ/mol) Type of interaction Interaction forces Reversible Long range, weak, low specificity Van der Waals Electrostatic 20-50 Irreversible Short rage, high specificity Dipole-dipole Dipole-induced dipole Ion-dipole Ionic Hydrogen... the catheters are minocycline-rifampin, piperacillin, gentamicin, and ofloxacin Silver indifferent forms (ion, compound, hydrogel, metallic) can be used inmedical devices The most common ones for invasive materials are chlorohexidine-silversulfadiazine and impregnated silver The studies showed that use ofmonociclyne-rifampin, ofloxacim and chlorohexidine-silver-sulfadiazine resulted in the least number . and Degradation of Polymeric Materials used in Biomedical Applications Biomedical Engineering, Trends in Materials Science 518 biofilms are involved in 65% of microbial infections in the body (Potera,. Biofilm Associated Infections and Degradation of Polymeric Materials used in Biomedical Applications Biomedical Engineering, Trends in Materials Science 516 Type of interaction Interaction forces. physical degradation. 516 Biomedical Engineering, Trends in Materials Science Prevention of Biofilm Associated Infections and Degradation of Polymeric Materials used in Biomedical Applications